Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[Cl:4][CH2:5][C:6]1([CH3:24])[O:10][N:9]=[C:8]([S:11][CH2:12][C:13]2[C:14]([C:20]([F:23])([F:22])[F:21])=[N:15][N:16]([CH3:19])[C:17]=2F)[CH2:7]1.O.[C:26](OCC)(=[O:28])C>CO>[Cl:4][CH2:5][C:6]1([CH3:24])[O:10][N:9]=[C:8]([S:11][CH2:12][C:13]2[C:14]([C:20]([F:23])([F:22])[F:21])=[N:15][N:16]([CH3:19])[C:17]=2[O:28][CH3:26])[CH2:7]1
Reactant: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(CCl)C2)c1F
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1c(CSC2=NOC(C)(CCl)C2)c(C(F)(F)F)nn1C

Procedure:
0.9 g (4.4 mmoles) of sodium methoxide (in the form of a 28% methanol solution) was added, at room temperature, into a solution of 1.0 g (2.9 mmoles) of 5-chloromethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline dissolved in 10 ml of methanol. The mixture was heated for refluxing for 5 hours, to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water and extraction with ethyl acetate was conducted. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order, and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 3.3 g (yield: quantitative) of 5-chloromethyl-3-(5-methoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmeth-ylthio)-5-methyl-2-isoxazoline.
Reaction SMILES: C([C:3](CC)(C([O-])=O)[C:4]([O-])=[O:5])C.[Na].[CH3:13][O:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[C:18]([CH:23]=[CH:24][C:25](=[O:27])[CH3:26])=[C:17]([O:28][CH3:29])[N:16]=1.[OH-].[K+]>C(O)C>[OH:5][C:4]1[CH2:3][CH:23]([C:18]2[C:19]([O:21][CH3:22])=[N:20][C:15]([O:14][CH3:13])=[N:16][C:17]=2[O:28][CH3:29])[CH2:24][C:25](=[O:27])[CH:26]=1
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Reactant: COc1nc(OC)c(C=CC(C)=O)c(OC)n1
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Product: COc1nc(OC)c(C2CC(=O)C=C(O)C2)c(OC)n1
Temperature: 90 °C
Yield: 69.1 %

Procedure:
Diethylmalonate (4.5 g) was added to a solution of sodium metal (0.65 g) in absolute ethanol (30 ml) and the mixture was heated under reflux with stirring. 1-(2,4,6-Trimethoxy-5-pyrimidylbut-1-en-3-one (6.4 g) was added and the mixture was then boiled under reflux for 2 hours. An aqueous solution of potassium hydroxide (3.5 g in 80 ml of water) was added and the mixture was heated under reflux for a further 5 hours. The solution was cooled and extracted with chloroform (50 ml) and then the aqueous layer was heated to 90° C. and carefully acidified (pH 4.5) with dilute aqueous hydrochloric acid. The resultant precipitate was removed by filtration to give 3-hydroxy-5-(2,4,6-trimethoxy-5-pyrimidyl)cyclohex-2-en-1-one (5.2 g) as a pale yellow crystalline solid, mp 215° C. (dec). Extraction of the filtrate with ethylacetate gave a further 0.7 g of product.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][C:15]=3[CH3:24])=[CH:7][C:6]=2[C:5]2[CH:25]=[CH:26][C:27]([CH3:29])=[CH:28][C:4]=2[N:3]=1.[OH-].[Na+]>CO.C(OCC)(=O)C.O>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=3[CH3:24])=[CH:7][C:6]=2[C:5]2[CH:25]=[CH:26][C:27]([CH3:29])=[CH:28][C:4]=2[N:3]=1
Reactant: COC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)O)cc3C)cc12
Temperature: 25 °C

Procedure:
A solution of methyl 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoate (from Example 115) (1.0 eq.), and 1N sodium hydroxide (1.5 eq.) in methanol (0.04 M) was stirred at 60° C. for 4 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and water. The two phases were separated. The organic layer was washed twice with water, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-50% ethyl acetate in hexane to give 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoic acid as a white solid.
Reaction SMILES: CC(S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O)C.[CH:16]1[C:21]([C@H:22]2[O:32][C:31]3[CH:30]=[C:29]([OH:33])[CH:28]=[C:27]([OH:34])[C:26]=3[C:24](=[O:25])[CH2:23]2)=[CH:20][CH:19]=[C:18]([OH:35])[CH:17]=1>>[OH:35][C:18]1[CH:17]=[CH:16][C:21]([CH2:22][CH2:23][C:24]([C:26]2[C:31](=[CH:30][C:29](=[CH:28][C:27]=2[OH:34])[OH:33])[OH:32])=[O:25])=[CH:20][CH:19]=1
Reactant: O=C1C[C@@H](c2ccc(O)cc2)Oc2cc(O)cc(O)c21
Agent: CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Product: O=C(CCc1ccc(O)cc1)c1c(O)cc(O)cc1O

Procedure:
To induce (over)expression initially an IPTG concentration of 1 mM in the medium is set and then 7 ml of a naringenin solution (100 mM in DMSO) added.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[OH:10][OH:11].[C:12](Cl)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:14])[CH3:13].C1(O)C=CC=CC=1>>[C:2]([O:10][O:11][C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:14])[CH3:13])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:1])[CH3:3]
Reactant: OO
Reactant: CC(C)(Cl)c1ccccc1
Reactant: C=C(C)c1ccccc1
Solvent: Oc1ccccc1
Product: CC(C)(OOC(C)(C)c1ccccc1)c1ccccc1

Procedure:
When the reaction was run using a 1:1 mole ratio of α-methylstyrene to hydrogen peroxide, the reaction was very exothermic during the addition of the cumyl chloride and about two thirds of the way through the addition an uncontrollable exotherm occurred and the reaction mixture spewed out of the reactor. The reaction was repeated using one half as much cumyl chloride and phenol. Under these conditions, the reaction was controllable but a low yield of dicumyl peroxide was obtained and a considerable amount of cumene hydroperoxide was generated. The results are summarized in Table I.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:11]3[C:12](=[O:15])[O:13][CH2:14][C:10]=3[C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.C[OH:26]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:16][C:11]3[C:12](=[O:15])[O:13][CH2:14][C:10]=3[C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:24])=[O:26])=[CH:19][CH:18]=2)=[CH:6][CH:7]=1
Reactant: CO
Reactant: CSc1ccc(-c2c(-c3ccc(F)cc3)sc3c2COC3=O)cc1
Solvent: ClCCl
Product: CS(=O)c1ccc(-c2c(-c3ccc(F)cc3)sc3c2COC3=O)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
2-(4-Fluorophenyl)-3-(4-(methylthio)phenyl)-4H-thieno [2,3-c]furan-6-one (548 mg) (from Step 4) was dissolved in 10 mL of 10:1 CH2Cl2 /-MeOH and treated with 476 mg of MPPM at 0° C. After stirring for 15 min at 0° C. and 1.5 h at room temperature, the reaction mixture was quenched with 20 mL of sat. NaHCO3, and extracted with 50 ml of EtOAc. The extract was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with EtOAc to give 490 mg of the title compound.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][CH2:8][CH2:9][SH:10].[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@@H:19]1[C:23](F)=[O:24])=[O:17])([CH3:14])([CH3:13])[CH3:12]>O.C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@@H:19]1[C:23](=[O:24])[NH:7][CH2:8][CH2:9][SH:10])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)F
Reactant: NCCS
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)NCCS
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a 50 mL round-bottom flask charged with a solution of sodium bicarbonate (134.3 mg, 1.6 mmol) in 7.8 mL water was added 2-aminoethanethiol hydrochloride (97.5 mg, 0.86 mmol). To this stirring solution was added dropwise over 60 seconds a solution of 25d (170.3 mg, 0.78 mmol) in 7.8 mL CH2Cl2. The reaction was vigorously stirred for 25 minutes at room temperature, then extracted twice with fresh CH2Cl2. The combined CH2Cl2 extracts were washed once with 5% aqueous HCl, once with 10% aqueous sodium bicarbonate, then once with water. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 205.8 mg (96% from 24d) of clean 26d as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[CH:5]=[N:4][C:3]=1[C:20]#[N:21].[CH:22]1([Mg]Br)[CH2:26][CH2:25][CH2:24][CH2:23]1.[CH2:29]1COCC1>>[CH:22]1([C:20]2[N:21]=[CH:29][N:1]=[C:2]3[C:3]=2[N:4]=[CH:5][N:6]3[C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:14][CH2:15]2)=[O:11])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Br[Mg]C1CCCC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc(C#N)c1N
Reactant: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(C3CCCC3)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
To a stirred solution of 3-(5-amino-4-cyano-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide (140 mg) in THF (25 mL, dry) under nitrogen at room temperature was added cyclopentylmagnesium bromide (2.5 mL, 2 M in diethyl ether). The mixture was stirred at room temperature for 3 hr before solvent was removed. The residue was redissolved in EtOAc, washed by water, brine, dried over Na2SO4, and concentrated. The residue was redissolved in MeOH (2.0 mL), HC(OMe)3 (2.0 mL) and TsOH (catalytic amount) were added. The mixture was irritated at 120° C. using microwave for 20 min. The solvent was removed and the crude product was purified by column chromatography on silica gel eluted with EtOAc, followed by further purifictaction by preparatory HPLC to give the title compound as a white solid (41.2 mg, 23%). HPLC tR=2.07 min; MS m/z 362.31 [M+H]+.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([CH2:8][CH2:9][CH2:10][CH2:11][B:12]([OH:14])[OH:13])[C:5]([OH:7])=[O:6].C(N(CC)CC)C.[C:28](OC(=O)C)(=[O:30])[CH3:29]>CN(C=O)C.Cl>[ClH:1].[NH2:3][C:4]([CH:15]1[CH2:16][CH2:17][N:18]([C:28](=[O:30])[CH3:29])[CH2:19][CH2:20]1)([CH2:8][CH2:9][CH2:10][CH2:11][B:12]([OH:14])[OH:13])[C:5]([OH:7])=[O:6]
Reactant: NC(CCCCB(O)O)(C(=O)O)C1CCNCC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(C(N)(CCCCB(O)O)C(=O)O)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 52.9 %

Procedure:
To a stirring solution of crude 2-amino-6-borono-2-(piperidin-4-yl)hexanoic acid dihydrochloride (Example 26-A, Step 1, 250 mg, 0.618 mmol) in dry DMF (13 mL) under nitrogen was added triethylamine (0.69 mL, 4.95 mmol) to give a white slurry. The resultant slurry was treated with acetic anhydride (0.131 mL, 1.39 mmol), added dropwise, and the reaction mixture was stirred at room temperature for 2.5 h. The mixture was then diluted with ice water (10 mL) and 3 N HCl (5 mL) prior to extraction with ethyl acetate (2×25 mL). The aqueous layer was concentrated under reduced pressure to give the crude product which was purified by reverse phase HPLC [Phenomenex Luna 250×30.00 mm, 10 micron column. 40 mL/min flow rate. Gradient: solvent A is 0.07% TFA in acetonitrile; solvent B is 0.10% TFA in water; 2% A for 2 min, 2% to 20% A over 23 min, then 20% to 100% A over 1 min.] Product fractions were pooled and concentrated, and the residue was taken up in 0.25N HCl (3 mL)/acetonitrile (8 mL) and concentrated. The residue was once again treated with 0.25N HCl (3 mL)/acetonitrile (8 mL) and concentrated and dried under high vacuum overnight to give 2-amino-6-borono-2-[1-acetylpiperidin-4-yl]hexanoic acid hydrochloride (110 mg, 53%) as a white solid. 1H NMR (D2O, 400 MHz) δ 4.38 (bt, J=12 Hz, 1H), 3.92 (bt, J=12 Hz, 1H), 3.03 (m, 1H), 2.55 (m, 1H), 2.11 (m, 1H), 2.00 (s, 3H), 1.87-1.78 (m, 3H), 1.55 (m, 1H), 1.50-1.00 (m, 6H), 0.68 (t, J=7.2 Hz, 2H). ESI+ MS found for C13H25BN2O5 m/z 583.3 (2M−18+H), 565.6 (2M−2×18+H), 283.4 (M−18+H), 265.3 (M−2×18+H); ESI− MS m/z 581.6 (2M−18−H), 299.4 (M−H), 281.4 (M−18−H).
Reaction SMILES: ClC1N=C(CI)C=C(N2CCOC[C@@H]2C)N=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].[Cl:22][C:23]1[N:28]=[C:27]([CH2:29][OH:30])[CH:26]=[C:25]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]2[CH3:37])[N:24]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:17][S:18]([O:30][CH2:29][C:27]1[CH:26]=[C:25]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]2[CH3:37])[N:24]=[C:23]([Cl:22])[N:28]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1COCCN1c1cc(CO)nc(Cl)n1
Agent: C[C@H]1COCCN1c1cc(CI)nc(Cl)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1COCCN1c1cc(COS(C)(=O)=O)nc(Cl)n1
Temperature: 25 °C
Yield: 100 %

Procedure:
2-Chloro-4-(iodomethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine can also be prepared by the dropwise addition of methanesulfonyl chloride (91 mL, 1169.52 mmol) to [2-chloro-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methanol (190 g, 779.68 mmol) and triethylamine (163 mL, 1169.52 mmol) in DCM (2293 mL) at 0° C. under air. The resulting solution was allowed to warm up slowly to RT over a period of 4 hours. The reaction mixture was quenched with water, extracted with DCM and the organic layer dried over MgSO4, filtered and evaporated to afford [2-chloro-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methyl methanesulfonate as a yellow gum (251 g). Sodium iodide (234 g, 1560.07 mmol) was added to this material in acetone (3679 mL) and the resulting suspension stirred at RT for 16 hours. The reaction mixture was evaporated to dryness and redissolved in DCM and washed three times with water then with a saturated aqueous solution of sodium thiosulphate. The organic layer was dried over MgSO4, filtered and evaporated to afford crude desired product (270 g). This was purified by chromatography to give an off white solid which was further triturated with ether to give the desired material which was identical to previous samples.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[O:7].[C:25]([NH:32][C@@H:33]([C:38](O)=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36])([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:38](=[O:39])[C@H:33]([NH:32][C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:34][CH:35]([CH3:37])[CH3:36])=[CH:21][CH:22]=1)[NH:5][C:6](=[O:7])[C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15]
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)c1c(C)cccc1Cl
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(NC(=O)[C@@H](CC(C)C)NC(=O)OC(C)(C)C)cc1)NC(=O)c1c(C)cccc1Cl
Yield: 102 %

Procedure:
A solution of 4-amino-N-[(2-chloro-6-methylphenyl)carbonyl]-L-phenylalanine methyl ester (561 mg, 1.61 mmol), prepared using procedure described in Example 68. in DMF (4.5 mL) was treated with N-Boc-D-leucine (393.2 mg, 1.7 mmol), HBTU (644.3 mg, 1.7 mmol) and DIPEA (0.62 mL, 3.50 mmol) at room temperature for 6 hr. The reaction mixture was diluted to 30 mL with water and the white precipitate was collected by filtration and was washed with water (2×2 mL). After drying under vacuum, the light yellow powder was recrystallized from ethyl acetate-hexane to give N-(2-chloro-6-methylbenzoyl)-4-[[(2R)-2-[(1,1dimethylethoxy)carbonyl]amino-4-methyl-1-oxopentyl]amino]-L-phenylalanine methyl ester (920 mg) as a white solid. MS 560 (M+H, 1 Cl). This solid was dissolved in 4 N HCl in dioxane (5 mL). The solution was stirred at room temperature overnight. After dilution with ether, the white suspension was allowed to stand at −5° C. for 1 hr. The white solid was collected by filtration and was dried under vacuum for 5 hr. The above solid was then dissolved in 20 mL of water and the solution was treated with sodium bicarbonate followed by K2CO3 to PH >9. The mixture was then extracted with dichloromethane (2×25 mL) and was dried over sodium sulfate. After removal of solvent, the residue was then dried under vacuum at 50° C. overnight to give white solid (520 mg, 1.1 mmol) in 70% overall yield. HRMS: Obs. 460.1997, Calc. 460.2003 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH:18]1[CH:22]=[CH:21][CH:20]=[N:19]1>>[N:18]1([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)[CH:22]=[CH:21][CH:20]=[N:19]1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: c1cn[nH]c1
Product: FC(F)(F)c1cc(-n2cccn2)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine (74 mg, 0.285 mmol) and pyrazole (28 mg, 0.425 mmol) similar to Example 166 and was isolated as a white solid (mp 151-152° C., 67 mg, 0.230 mmol, 81%). 1H NMR (CDCl3) 9.71 (s, 1H), 8.77 (m, 3H), 8.19 (s, 1H), 7.88 (m, 1H), 7.47 (m, 1H), 6.61 (dd, J=1.5, 2.7 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][C:4](=[O:7])[CH:3]=1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[F:17])[CH:12]=O.[CH2:18]([N:25]1[CH2:30][C:29](=O)[CH2:28][C:27](=[O:32])[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH2:18]([N:25]1[CH2:30][C:29]2[NH:1][C:2]3[CH2:6][CH2:5][C:4](=[O:7])[C:3]=3[CH:12]([C:11]3[CH:14]=[CH:15][C:16]([F:17])=[C:9]([Cl:8])[CH:10]=3)[C:28]=2[C:27](=[O:32])[CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C1CC(=O)CN(Cc2ccccc2)C1
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: NC1=CC(=O)CC1
Solvent: CCO
Product: O=C1CCC2=C1C(c1ccc(F)c(Cl)c1)C1=C(CN(Cc3ccccc3)CC1=O)N2

Procedure:
A mixture of 3-amino-2-cyclopenten-1-one (Kikani, B. B., Synthesis, (1991), 2, 176) (0.78 g, 8 mmol), 3-chloro-4-fluorobenzaldehyde (1.12 g, 8 mmol), and N-benzylpiperidine-3,5-dione (Ziegler, J. Amer. Chem. Soc. (1973), 95, 7458-7464) (1.78 g, 8 mmol) in ethanol (8 mL) was processed in Example 5A to provide 1.8 of the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][N:8]1[CH:12]=[N:11][N:10]=[CH:9]1.F[C:14]1[CH:15]=[CH:16][C:17]2[C:18]([CH:22]=1)=[N:19][O:20][N:21]=2.O>CS(C)=O>[N:11]1[N:10]=[CH:9][N:8]([NH:7][C:14]2[CH:15]=[CH:16][C:17]3[C:18]([CH:22]=2)=[N:19][O:20][N:21]=3)[CH:12]=1
Reactant: Fc1ccc2nonc2c1
Reactant: Nn1cnnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: c1cc2nonc2cc1Nn1cnnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
26.70 Grams of potassium tert-butoxide was dissolved in 100 ml of anhydrous dimethylsulfoxide and 20.00 g of 4-amino-4H-1,2,4-triazole was added thereto, followed by stirring for 2 hours at room temperature. Next, 50 ml of an anhydrous dimethylsulfoxide solution containing 11.00 g of 5-fluorobenzofurazane was added dropwise to the solution over a period of 20 minutes and then the mixture was stirred for 15 minutes. The reaction mixture was poured into 500 ml of water and 500 g of ice and then washed with 200 ml of ethyl acetate. The solution was then adjusted to have pH of 7.0 with 1N hydrochloric acid to give crystals. The crystals were collected by filtration, and the remaining mother liquid was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the crude crystals thus obtained were recrystallized from ethanol. These were combined with the previously obtained crystals to give 12.49 g of 5-[(4H-1,2,4-triazol-4-yl)amino]benzofurazane.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)[CH2:13][CH2:14][CH3:15].[F-].[Cs+]>O1CCOCC1>[CH2:12]([C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=2)=[CH:18][CH:17]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1ccc(B(O)O)cc1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: CCCCc1ccc(-c2ccc(N)c([N+](=O)[O-])c2)cc1
Temperature: 120 °C

Procedure:
A Smith Process Vial charged with 4-bromo-2-nitroaniline (205 mg, 0.945 mmol), 4-butyl phenyl boronic acid (336 mg, 1.89 mmol), cesium fluoride (430 mg, 2.83 mmol), bis(tri-t-butyl-phosphine)-palladium (24.1 mg, 0.0472 mmol), and dioxane (2 ml) is purged with Argon (g) for 5 minutes and then heated in a microwave to 120° C. for 15 minutes. The crude reaction is filtered through Celite using EtOAc as eluent. The filtrate is concentrated in vacuo and the crude product is purified with silica gel flash column chromatography (0-100% ethyl acetate in hexanes gradient) to afford 4′-butyl-3-nitro-biphenyl-4-ylamine: ESMS m/z 271.2 (M+H+).
Reaction SMILES: [CH2:1](OS(C)(=O)=O)[CH2:2][CH2:3][CH3:4].[N:10]1([C:16]2[C:17](=[O:34])[N:18]([CH2:22][CH2:23][O:24][C:25]3[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:26]=3[F:33])[CH:19]=[CH:20][N:21]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Cl.N1(C2C(=O)N(CCOC3C=C(F)C(F)=CC=3F)C=CN=2)CCNCC1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCOC(C)=O.O>[F:33][C:26]1[CH:27]=[C:28]([F:32])[C:29]([F:31])=[CH:30][C:25]=1[O:24][CH2:23][CH2:22][N:18]1[CH:19]=[CH:20][N:21]=[C:16]([N:10]2[CH2:15][CH2:14][N:13]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:12][CH2:11]2)[C:17]1=[O:34]
Reactant: O=c1c(N2CCNCC2)nccn1CCOc1cc(F)c(F)cc1F
Reactant: CCCCOS(C)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCN1CCN(c2nccn(CCOc3cc(F)c(F)cc3F)c2=O)CC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Methanesulfonic acid butyl ester (0.30 g, 1.97 mmol; from Step 1) was added to a mixture of 3-(1-piperazinyl)-1-[2-(2,4,5-trifluorophenoxy)ethyl]-2(1H)-pyrazinone (0.50 g, 1.4 mmol; from the free base of Example 3) and potassium carbonate (0.10 g, 2.89 mmol) in DMSO (3 g). After being stirred for 3 h at 60° C., water (50 g) and EtOAc (100 g) were added to the reaction mixture. The layers were separated and the organic layer was concentrated in vacuo. The residue was purified by chromatography on a MPLC column using a continuous gradient (0-100% EtOAc in heptane) as eluent. This furnished 33 mg (8%) of the title compound as an oil. 1H NMR analysis supports the stated structure. HPLC purity: 100%. HRMS m/z calcd for C20H25F3N4O2 (M)+ 410.1930, found 410.1920.
Reaction SMILES: C(O[C:4]([CH:6]([O:8][C:9]1[N:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=1)[CH3:7])=[O:5])C.[CH3:20][NH2:21]>CN(C)C=O>[CH3:20][NH:21][C:4]([CH:6]([O:8][C:9]1[N:13]=[CH:12][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:10]=1)[CH3:7])=[O:5]
Reactant: CN
Reactant: CCOC(=O)C(C)Oc1ncn(-c2ccccc2)n1
Solvent: CN(C)C=O
Product: CNC(=O)C(C)Oc1ncn(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
A 2.5 g portion of the compound of Example 1 was combined with 10 ml of 40% aqueous methylamine and 20 ml of dimethylformamide at room temperature, and the mixture was allowed to stand for 2 days. It was then poured into ice-water, and the solid was collected and air-dried to obtain 0.4 g of the desired product, m.p. 134°-135°.